Effects of bombesin on methadone-induced apoptosis of human lung cancer cells

Cancer Lett. 1999 Mar 1;136(2):177-85. doi: 10.1016/s0304-3835(98)00335-8.

Abstract

The therapeutic opioid methadone, used to treat cancer pain and opioid addiction, is also a potent inducer of apoptosis in human lung cancer cells, thereby inhibiting their growth. However, in contrast to its central nervous system (CNS) actions, this effect appears to be mediated through a non-opioid mechanism involving bombesin, an autocrine growth-stimulatory factor that plays a central role in the early events of pulmonary carcinogenesis. Exposure of 'variant' small cell lung carcinoma (SCLC) and non-SCLC cells, which secrete low concentrations (< 0.01 pmol/mg protein) of bombesin, to nanomolar concentrations of methadone resulted in increased levels of mitogen-activated protein (MAP) kinase phosphatases and inactivation of MAP kinase, suppression of the bcl-2 protein, and induction of apoptosis. These effects of methadone were reversed by the addition of bombesin to the culture medium, at concentrations of < 1 microM, and 'classic' SCLC cells, which secrete high concentrations of bioactive bombesin (> 6 pmol/mg protein), were found not to respond to methadone. Thus, methadone's effectiveness is dependent upon the concentration of bioactive bombesin secreted by lung cancer cells. Methadone treatment suggests a novel therapeutic approach for patients presenting 'variant' SCLC and non-SCLC morphologies, since they respond less to conventional therapy.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Apoptosis*
  • Blotting, Western
  • Bombesin / pharmacology*
  • Calcium-Calmodulin-Dependent Protein Kinases / antagonists & inhibitors
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism
  • Carcinoma, Non-Small-Cell Lung / enzymology
  • Carcinoma, Non-Small-Cell Lung / pathology*
  • Carcinoma, Small Cell / enzymology
  • Carcinoma, Small Cell / pathology*
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / pharmacology
  • Flavonoids / pharmacology
  • Humans
  • Lung Neoplasms / enzymology
  • Lung Neoplasms / pathology*
  • Methadone / pharmacology*
  • Mitogen-Activated Protein Kinase 1
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Signal Transduction / drug effects
  • Tumor Cells, Cultured

Substances

  • Enzyme Inhibitors
  • Flavonoids
  • Proto-Oncogene Proteins c-bcl-2
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Mitogen-Activated Protein Kinase 1
  • Bombesin
  • 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
  • Methadone